M protein, a fibrillar molecule on the surface of the group A streptococcus, protects the organism from attack by human phagocytic cells and is therefore considered to be the major virulence factor for this bacterium. While anti-M protein antibodies protect against subsequent streptococcal infection, this protection is specific for organisms of one serotype of M protein. (Over 80 serotypes are currently recognized.) To approach the question of broad protection from infection by group A streptococci, an understanding of the relation of the molecular structure of M proteins to their function is important. In our previous work, we reported the first M protein gene sequence and determined one molecular mechanism for antigenic variation. We also developed the genetic techniques necessary to perform a detailed structure-function analysis of this virulence factor. This analysis, the first goal of this work, will provide a rational basis for possible vaccine development. In addition, we have identified a gene (mry) that encodes a protein required for expression of the M protein and possibly of other virulence factors of S. pyogenes. The predicted structure of Mry suggests that it is part of a signal-transducing system and it is possible that, like proteins of this type in other pathogenic bacteria, Mry may be a global regulator of streptococcal virulence determinants. We propose to utilize molecular genetics to analyze the mechanism of the environmentally responsive regulation by Mry. It may be possible to develop an anti-bacterial agent based on a better understanding of the mode of action of this protein. It seems likely that a functional mry gene is also present in other group A streptococcal strains and may be required for their virulence. In this case, an antagonist to Mry should have antibacterial activity against all S. pyogenes strains regardless of M type. Furthermore, because signal- transducing systems of different organisms have many features in common, an antagonist to Mry might have activity against a broad spectrum of different pathogenic bacteria.